The overarching goal of this research is to determine the role of a specific calcium permeable subtype of AMPA glutamate receptors (unedited GluA2 (Q)) in the nucleus accumbens as a critical and novel mechanism underlying relapse to cocaine abuse. Importantly, this proposal aims to explore adenosine deaminase acting on RNA 2 (ADAR2), the enzyme involved in GluA2 editing, as a novel target as the basis for the future development of therapies to combat addiction. AMPA receptors are tetrameric protein complexes that consist of GluA1-GluA4 subunits, of which GluA2 imparts calcium permeability. The ability of the GluA2 subunit to regulate calcium influx depends upon RNA editing. GluA2 transcripts are edited by ADAR2 such that the genomic glutamine (Q) codon is converted to a codon encoding arginine (R). Thus, AMPA receptors are calcium-impermeable if they contain the edited GluA2(R) subunit and calcium- permeable if they contain the unedited GluA2(Q) subunit or if they are GluA2-lacking. Emerging evidence suggests that the reinstatement of cocaine seeking is associated with increased cell surface expression of calcium-permeable AMPA receptors (i.e., GluA2-lacking AMPA receptors) in the accumbens shell that is associated with the reinstatement of cocaine seeking. However, repeated exposure to cocaine does not alter GluA1 or GluA2 mRNA levels in the nucleus accumbens highlighting the importance of post-transcriptional regulation of AMPA receptor subunit function for cocaine addiction. The project proposed here will investigate the role of ADAR2 and AMPA GluA2 editing within the nucleus accumbens during abstinence versus extinction from cocaine specifically as an important mechanism underlying vulnerability to relapse. Our preliminary data in rodents show that during a week of abstinence from cocaine self- administration, there is a decrease in edited GluA(R) levels that translates into more calcium-permeable GluA2(Q) receptors, and a decrease in ADAR2 levels in the nucleus accumbens shell. These are the first findings to demonstrate these alterations as associated with drug abuse. We also demonstrated that increasing ADAR2 levels using viral vector delivery into the accumbens shell reduces reinstatement to cocaine. These findings unveil ADAR2 as a novel target for inhibiting drug seeking as increasing ADAR2 levels blunted cocaine's reinforcing effects. Therefore we hypothesize that: 1) cocaine alters ADAR2 expression in the nucleus accumbens thereby increasing calcium permeable GluA2 receptors, and 2) increased calcium permeable GluA2 receptors enhance the reinstatement to cocaine seeking in an animal model of relapse. These hypotheses will be investigated in this proposal. We believe that determining the role of ADAR2 in cocaine-seeking can help to prevent relapse as it could serve as a novel therapeutic target for the treatment of cocaine addiction.